The CLDNs are integral membrane proteins associated with tight junctions (TJs). TJs are located at the most apical region of the lateral membrane in epithelial cell and endothelial sheets. Their two major functions are a fence function that maintains cell polarity and a paracellular barrier function that regulates the diffusion of solutes (Tsukita and Furuse, 2006). CLDNs interact in two different ways: laterally in the plane of the membrane (heteromeric interactions) or head to head binding between adjacent cells (heterotypic interactions). They can form a complex with occludin and/or JAMs. They have a short intracellular N-terminal domain, four transmembrane domains, two extracellular loops and an intracellular C-terminal domain containing a phosphorylation site and a PDZ-domain-binding motif that allows claudins to interact directly with cytoplasmic scaffold proteins, such as the TJ-associated proteins MUPP1, PATJ, ZO-1, ZO-2 and ZO-3, and MAGUKs (Lal-Nag and Morin, 2009). These proteins might function as adaptors at the cytoplasmic surface of tight-junction strands to recruit other proteins including cytoskeletal and signalling molecules (Tsukita et al., 2001). A number of other cytosolic and nuclear proteins which includes regulatory proteins Rab3b, Rab13, tumor suppressors like PTEN, transcription factors like ZONAB, and HuASH1 have also been shown to interact directly or indirectly with tight junction complex (Singh et al., 2010).
CLDN1 belongs to the claudin family of proteins which consists of 24 members of closely related transmembrane proteins. CLDN1 is an emerging therapeutic target in colorectal cancer (Kominsky, 2006). CLDN1 was found overexpressed in tumor tissue compared to normal colon mucosa in several studies (including our study) and associated with tumor progression (Miwa et al., 2001; Dhawan et al., 2005; Grone et al., 2007; Huo et al., 2009). The participation of CLDN1 to neoplasia could be explained by the alteration of TJ structure and function due to aberrant tissue expression of CLDN1 or by the involvement of CLDN1 in cell signaling pathways (Singh et al., 2010). Dhawan and collab., have reported that the increase of CLDN1 in colon tumor tissues is accompanied by a delocalisation of CLDN1 from the membrane to the cytoplasm and nucleus (Dhawan et al., 2005). It was also suggested that CLDN1 could have a dual role: cell adhesion when located in the membrane and signal transduction when they are localized in the cytoplasm or the nucleus (Singh et al., 2010). Since the prior art stipulated that CLDN1 is delocalized from the membrane during tumor progression, the one skilled in the art was not able to envisage that immunotherapy based on anti-CLDN1 antibody was credible.